Stable benzimidazole formulation

ABSTRACT

A benzimidazole formulation which lacks an intermediate layer and yet which is stable both during storage and during the passage through the stomach, and which has low levels of residual volatile excipients, including but not limited to residual alkalinizing agents and/or residual solvents.

FIELD OF THE INVENTION

The present invention relates to a novel stable formulation for an acidlabile benzimidazole, and methods of preparation and administrationthereof, and in particular, for a stable formulation of a benzimidazolewhich is suitable for oral administration, and has low levels ofresidual volatile excipients such as solvents.

BACKGROUND OF THE INVENTION

Omeprazole, Pantoprazole, Lansoprazole and other derivatives ofbenzimidazole, which are active proton pump inhibitors and usedconventionally for decreasing gastric secretion are known to besusceptible to degradation and transformation in acid media. Omeprazole,5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-1H-benzimidazole,is disclosed and described in European Patent No. 5129 and EuropeanPatent No. 124495, as well as in numerous other patents and publishedpatent applications.

The susceptibility of these active proton pump inhibitor substances todegradation and transformation in acid media increases the difficulty ofpreparing a pharmaceutical form designed for oral administration. If theactive substance comes into contact with the stomach content, which is ahighly acidic medium, these chemical substances become degraded. Thus,these benzimidazole derivatives should be protected both during storageand during their passage through the acidic environment of the stomach.

The stability of Omeprazole has been extensively studied (see forexample A. Pilbrant and C. Cederberg, Scan. J. Gastroenterol., 20:113-120, 1985). Omeprazole degrades with a half-life of less than 10minutes in an environment with pH values below 4.0. At pH 6.5, the halflife of Omeprazole is 18 hours and at pH 11 about 300 days. Therefore,the environment of Omeprazole should be kept at a sufficiently high pHvalue in order to maintain the stability of the compound, in aformulation which is suitable as a product for oral administration, forexample by locating Omeprazole within a core which also containsalkaline constituents. This leads to an alkaline reaction aimed atimproving stability of the active substance during manufacture thereofand during storage of the pharmaceutical formulation.

In addition, such a formulation must protect Omeprazole from the acidicenvironment of the stomach, since if Omeprazole is given orally withoutany protective coating, it will degrade in the acid environment of thestomach. European Patent No. 237,200 discloses one solution, which is todirectly coat the solid core containing Omeprazole, or anotherbenzimidazole derivative, with an enteric coating layer.

However, this apparent solution to the instability of Omeprazole causedfurther complications, in that the alkaline core containing Omeprazolewas found to react with the enteric coating, thereby causing the entericcoating to degrade. A solution to these further complications isdisclosed in United Kingdom Patent Application No. 2,189,698, in whichOmeprazole is contained within a solid active core, which is coatedfirst with a subcoating layer and then with an enteric coating layer.The enteric coating layer protects the Omeprazole during the passagethrough the stomach, while the subcoating layer protects the entericcoating layer from reacting negatively with the alkaline core containingOmeprazole.

The background art describes other attempts to provide formulationswhich are suitable for oral administration of acid-labile substances.For example, PCT Application No. WO 97/12581 discloses a compositionadapted for oral administration containing Omeprazole which specificallydoes not include alkaline-reacting compounds. Instead, the compositionfeatures a core composed of a nuclei and Omeprazole compressed together,an intermediate layer and an enteric layer.

European Patent Application No. 519,144 discloses a formulation forOmeprazole, which features a neutral (sugar) core. Omeprazole is sprayedonto the sugar core, after which an intermediate coating layer and anenteric coating layer are sprayed onto the core.

PCT Application No. WO 98/00114 discloses a modification to otherbackground art formulations for Omeprazole, in which the intermediatesubcoating layer is partially neutralized with an alkaline compound.However, this modified formulation still features the subcoating layer,which is a disadvantage in that it complicates the manufacturing processand increases the expense and difficulty of manufacture. Thus, theformulation disclosed in PCT Application No. WO 98/00114, like thosedisclosed in European Patent Application No. 519,144 and otherbackground art references, has the disadvantage of requiring theintermediate layer.

PCT Application No. WO 83/00435 discloses a solid dosage form, such as acapsule or tablet, containing a pharmacologically active agent coatedwith an anionic polymer, which is insoluble in gastric juice and inintestinal juice below pH 7. The preferred anionic polymer is a partlymethyl esterified methacrylic acid polymer in which the ratio of freecarboxylic groups to ester groups is about 1:2. In contrast to thepresent invention, Omeprazole is not disclosed as one of the activeagents.

French Application No. 2,692,146 discloses stable compositions ofmicrogranules of gastro-protected Omeprazole. The composition features acenter of Omeprazole diluted in mannitol. This center is coated with anintermediate layer featuring mannitol. An enteric coating is then addedover this intermediate layer. PCT Application No. WO 97/12581 disclosesa formulation in which an intermediate layer between the core and anenteric coating contains silicium dioxide.

PCT Application No. WO 96/37195 discloses a formulation which lacks asubcoating layer, but which features a core containing titanium dioxide.Both the core containing Omeprazole and the enteric coating layer placedon top of the core include titanium dioxide as an ingredient.Unfortunately, titanium dioxide is only able to mask the discolorationcaused by the reaction between Omeprazole and the enteric coating layer,but cannot prevent such an undesirable reaction. Thus, the disclosedformulation does not prevent the undesirable reaction between thebenzimidazole derivative and the enteric coating, which is known in theart.

German Patent Application No. 196 26 045 A1 discloses a method forstabilising Omeprazole by coating small tablets or pellets, containinglarge amounts of mannitol, with a subcoating of Eudragit L. Thesubcoating of Eudragit L is neutralized, after which a final entericcoat of non-neutralized Eudragit L is applied.

A formulation of a benzimidazole derivative, such as Omeprazole, whichlacks an intermediate coating layer and yet which is stable both duringstorage and during the passage through the stomach, is described in U.S.patent application Ser. No. 10/018,992. This formulation involvesneutralization of the enteric coating with an alkaline compound, such asammonium hydroxide. The formulation is simple to manufacture and exposesthe sensitive benzimidazole derivative to fewer production steps,thereby decreasing degradation of the active compound during production.

However, neutralization of enteric coatings with an alkalinizing agentusually results in a certain amount of the alkalinizing agent remainingin the final product. Furthermore, benzimidazole formulations arefrequently prepared using volatile organic solvents, a residual amountof which is also found in the final product. Since there is notherapeutic benefit from residual alkalinizing agents and residualsolvents, and these may, in fact, have a harmful effect, it is desirableto keep the levels of such residual solvents as low as possible fortoxicity/safety reasons.

SUMMARY OF THE INVENTION

The background art does not teach or suggest a benzimidazoleformulation, particularly for Omeprazole, which lacks an intermediatelayer and yet which is stable both during storage and during the passagethrough the stomach, and which has low levels of residual alkalinizingagents and residual solvents.

The present invention overcomes these drawbacks of the background art byproviding a benzimidazole formulation which lacks an intermediate layerand yet which is stable both during storage and during the passagethrough the stomach, and which has low levels of residual volatileexcipients, including but not limited to residual alkalinizing agentsand/or residual solvents.

According to some embodiments of the present invention, there isprovided a stable composition for a benzimidazole derivative, thecomposition comprising a substrate, comprising the benzimidazolederivative; and a single coating layer consisting essentially of atleast one neutralized enteric polymer, the enteric polymer having beenneutralized by an alkalizing agent. The alkalizing agent is selectedfrom the group consisting of amino alcohols, alkylene diamines, ammoniasolution, arginine and lysine. Optionally and preferably there is asingle coating layer layered directly over the substrate, without anintermediate layer between the substrate and the enteric coating. Thecomposition comprises less than about 500 parts per million of residualalkalizing agent relative to the total weight of the composition.

According to some embodiments of the present invention, there isprovided a stable composition for a benzimidazole derivative, thecomposition comprising a substrate comprising the benzimidazolederivative and a single coating layer consisting of one or more entericpolymers treated by at least one volatile alkalizing agent prior toapplying over the substrate. The composition comprises less than 500parts per million of residual volatile alkalizing agents relative to thecomposition weight, and a pH of the coating layer is in the range offrom about 4.5 to about 6.5 as measured in 30 ml of distilled water at20-25° C.

Optionally and preferably, the pH is in the range of from about 5 toabout 6; more preferably the pH is about 5.

Optionally and preferably, the alkalizing agent comprises at least oneof basic sodium, potassium, methanolamine, ammonium solution (such asammonium hydroxide), amino alcohols (such as methanolamine, monoethanolamine, or propanolamine, or combinations thereof), arginine, lysine, andalkylene diamines (such as methylene diamine, ethylene diamine, orpropylene diamine, or combinations thereof).

Optionally and preferably, the enteric polymer is dissolved in anorganic solvent prior to application. Optionally and preferably, such acomposition comprises less than about 1000 parts per million of residualorganic solvent.

Non-limiting examples of organic solvents include acetone, ethanol,isopropanol or a mixture thereof.

Non-limiting examples of enteric polymers include cellulose acetatephthalate (CAP); hydroxypropyl methylcellulose phthalate (HPMCP);polyvinyl acetate phthalate; cellulose acetate trimellitate;poly((methacrylic acid, methyl methacrylate) 1:1) (Eudragit L000™),poly((methacrylic acid, ethyl acrylate) 1:1) (Eudragit L30D-55) orEudragit L100-55™, (poly(methacrylic acid, methyl methacrylate) 1:2)Eudragit™ S hydroxypropyl methylcellulose acetate succinate (HPMCAS),sodium alginate, and alginic acid or mixtures thereof.

Optionally and preferably, the substrate is an active core forcontaining the benzimidazole derivative, such as, for example, a pellet,a bead or a tablet.

Optionally and preferably, the active core is a tablet formed bycompression.

According to some embodiments of the present invention, the substratefeatures a neutral core; and an active coating containing thebenzimidazole derivative, wherein the active coating is layered over theneutral core; such that the composition is in a form of a pellet.

Optionally and preferably, the substrate features a core containing thebenzimidazole derivative with a suitable binding agent, the core beingprepared by spheronisation and pelletization; such that the compositionis in a form of a pellet.

The benzimidazole is optionally one or more of Omeprazole, Pantoprazole,Lansoprazole, Leminoprazole, Perprazole, Rabeprazole, orpharmaceutically acceptable salts thereof, or combinations thereof.

Optionally, the substrate further comprises a filler, such as, forexample, one or more of microcrystalline cellulose, sodiumcarboxymethylcellulose, ethylcellulose, cellulose acetate, starch,lactose, glucose, fructose, sucrose, dicalcium phosphate, sorbitol,mannitol, mantitol, lactitol, xylitol, isomalt, erythritol, andhydrogenated starch hydrolysates, or a mixture thereof.

Optionally, the substrate further comprises a disintegrant, such as, forexample, one or more of low-substituted carboxymethyl cellulose sodium,cross-linked polyvinyl pyrrolidone, sodium starch glycolate,cross-linked sodium carboxymethyl cellulose, pregelatinized starch,microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, and low substituted hydroxypropyl cellulose magnesiumaluminum silicate, or a mixture thereof.

Optionally, the substrate further comprises a lubricant, such as, forexample, one or more of sodium stearyl fumarate, polyethylene glycol,silica colloidal anhydrous and magnesium stearate, or a mixture thereof.

Optionally, the substrate further comprises an alkalinizing agent, suchas, for example, one or more of sodium stearate, meglumine, disodiumphosphate, and ammonia, or a mixture thereof.

Optionally, the coating layer further comprises a plasticizer, such as,for example, one or more of a citric acid ester and a phthalic acidester.

Optionally, the coating layer further comprises a surfactant, such as,for example, one or more of polysorbate 80 and sodium lauryl sulfate.

Optionally, the coating layer further comprises a glidant, such as, forexample one or more of talc and titanium dioxide.

Optionally, the coating layer further comprises at least one of acoloring agent and a polishing agent.

According to some embodiments there is provided a method for preparing astable composition for a benzimidazole derivative, the method comprisingneutralizing one or more enteric polymers with at least one volatilealkalizing agent; and layering the enteric polymer(s) over a substratecomprising the benzimidazole derivative to form a coating layer, thecomposition comprising the substrate and the coating layer, such thatthe composition comprises less than 1000 parts per million of residualvolatile alkalizing agents relative to composition weight.

Optionally, the alkalizing agent comprises one or more of aminoalcohols, alkylene diamines, arginine, lysine, and ammonia solution.

According to some embodiments, there is provide a method for preparing astable composition for a benzimidazole derivative, the method comprisingdissolving one or more enteric polymers in an organic solvent;neutralizing the enteric polymer(s) with at least one volatilealkalizing agent; and layering the enteric polymer(s) over a substratecomprising the benzimidazole derivative to form a coating layer, thecomposition comprising the substrate and the coating layer, such thatthe composition comprises less than 1000 parts per million of residualsolvent relative to composition weight.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, withreference to the accompanying drawings. With specific reference now tothe drawings in detail, it is stressed that the particulars shown are byway of example and for purposes of illustrative discussion of thepreferred embodiments of the present invention only, and are presentedin the cause of providing what is believed to be the most useful andreadily understood description of the principles and conceptual aspectsof the invention. In this regard, no attempt is made to show structuraldetails of the invention in more detail than is necessary for afundamental understanding of the invention, the description taken withthe drawings making apparent to those skilled in the art how the severalforms of the invention may be embodied in practice.

In the drawings:

FIGS. 1-6 relate to the suitability of test method for determination ofresidual monoethanolamine.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The formulation of the present invention contains a benzimidazolederivative, such as Omeprazole, and is able to maintain the stability ofthis active ingredient without a separating layer between the activecompound and an enteric coating layer. Instead, the enteric coatinglayer is prepared as an aqueous dispersion or in organic solvent andneutralized with an alkalinizing agent, before being applied as asolution directly to the benzimidazole derivative substrate.

Preferably, the aqueous dispersion has a pH in the range of at least6.5, and more preferably in the range of from about 7 to about 10.

After being applied to the substrate, the aqueous dispersion dries toform a coating layer, preferably having a pH in the range of from about4.5 to about 6.5, and more preferably from about 5 to about 6, asmeasured in 30 ml of distilled water at 22° C.

The resulting formulation comprises less than about 500 parts permillion of residual alkalizing agent relative to the total weight of thecomposition.

Preferably, the composition comprises less than about 1000 parts permillion of residual organic solvent and more preferably less than about500 ppm.

The resultant formulation maintains the stability of the benzimidazolederivative during storage and at the same time protects the productduring passage through the acidic environment of the stomach. Theproblem of interaction between the enteric coat and the alkaline core isthus completely eliminated as the enteric coat at this stage does notrelease the free protons that are responsible for its acidic properties.At the same time, the formulation has low levels of residualalkalinizing agent and residual organic solvent in the final product.

The preparation of the benzimidazole-containing compositions of thepresent invention is described first with reference to the followinggeneral description and then with reference to the followingnon-limiting examples of the preparation and application of thecompositions of the present invention.

The formulation of the present invention includes a substrate whichfeatures the benzimidazole derivative. A coating suspension, which has apH value of at least 6.5 and more preferably of from about 7 to about10, is prepared with the enteric coating material. Preferably, a pHvalue in the desired range is obtained by adding an alkalinizing agentto an enteric coating material

More preferably, the alkalinizing agent is selected from the groupconsisting of basic sodium, potassium, methanolamine or ammoniumhydroxide, amino alcohols and alkylene diamines, arginine, and lysine.This enteric coating solution is then layered directly over thesubstrate to form the composition of the present invention.

The term “substrate” refers to substantially any structure whichfeatures the benzimidazole derivative, such as Omeprazole. For example,this structure could be an active core containing the benzimidazolederivative. The active core may comprise, for example, a pellet, a bead,or a tablet. This active core could be prepared in a number of differentways which are known in the art. For example, the active core could beformed by compressing the benzimidazole derivative with an alkalinesubstance. As another example, the active core could be prepared bymixing the benzimidazole derivative with an alkaline substance,spheronizing the mixture and then forming cores through pelletisation.As yet another example, the active core is optionally and preferablyprepared by embedding the active ingredient in a poloxamer andcompressing the embedded material into tablets. The active core is alsooptionally formed by granulating the active ingredient with an alkalinesubstance and compressing the granulation into tablets.

Alternatively and optionally, the structure could include a neutralcore, such as a sugar bead which does not contain the benzimidazolederivative, over which the benzimidazole derivative is coated. Thecoating includes Omeprazole or other benzimidazole derivative with asuitable adhesive polymer. The pellet may optionally be prepared byspheronization and pelletization of the benzimidazole derivative and asuitable binding agent.

The benzimidazole derivative of the present invention may comprise, forexample, Omeprazole, Pantoprazole, Lansoprazole, Leminoprazole,Perprazole, or Rabeprazole, or pharmaceutically acceptable saltsthereof. Preferably, the benzimidazole derivative is omeprazole.

Optionally, the substrate may further comprise a filler. Examples ofsuitable fillers include microcrystalline cellulose, sodiumcarboxymethylcellulose, ethylcellulose, cellulose acetate, starch,lactose, glucose, fructose, sucrose, dicalcium phosphate, sorbitol,mannitol, mantitol, lactitol, xylitol, isomalt, erythritol, andhydrogenated starch hydrolysates, or a mixture thereof.

Further optionally, the substrate may comprise a disintegrant, such as,for example, low-substituted carboxymethyl cellulose sodium,cross-linked polyvinyl pyrrolidone, sodium starch glycolate,cross-linked sodium carboxymethyl cellulose, pregelatinized starch,microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, and low substituted hydroxypropyl cellulose magnesiumaluminum silicate, or a mixture thereof.

Also optionally, the substrate may further comprise a lubricant, suchas, for example, sodium stearyl fumarate, polyethylene glycol, silicacolloidal anhydrous and magnesium stearate, or a mixture thereof.

The substrate may optionally further comprises an alkalinizing agent,such as, for example, sodium stearate, meglumine, disodium phosphate,magnesium carbonate, and ammonia, or a mixture thereof.

Substantially any type of neutralized suitable enteric coating materialcould be used in order to coat the benzimidazole substrate, includingbut not limited to, cellulose acetate phthalate (CAP); hydroxypropylmethylcellulose phthalate (HPMCP); polyvinyl acetate phthalate;cellulose acetate trimellitate; poly((methacrylic acid, methylmethacrylate) 1:1) (Eudragit L100™, poly((methacrylic acid, ethylacrylate) 1:1) (Eudragit L30D-55) or Eudragit L100-55™,(poly(methacrylic acid, methyl methacrylate) 1:2) Eudragit™,hypromellose acetate succinate (HPMCAS), sodium alginate, and alginicacid or mixtures thereof.

As used herein, the term “neutralized enteric coating material” refersto enteric coating material which has been at least partiallyneutralized by reaction with an alkalizing agent. Suitable alkalizingagents for neutralizing the enteric polymer include, but are notlimited, to amino alcohols such as methanolamine, monoethanol amine,propanolamine and alkylene diamines such as methylene diamine, ethylenediamine, propylene diamine, and ammonia solution such as ammoniumhydroxide, basic ammonium salts, arginine, lysine and any otherpharmaceutically acceptable amino compound bases, or a combinationthereof.

Preferably, the enteric coating material is at least about 60%neutralized, more preferably the enteric coating material is at leastabout 80% neutralized, and most preferably the enteric coating materialis at least about 95% neutralized.

The enteric coating is optionally prepared in an organic solvent, suchas, for example, acetone, ethanol or isopropanol, or a combinationthereof; such as a mixture of ethanol and water (30/70 or 40/60); or amixture of isopropyl alcohol and ethanol.

The enteric coating optionally contains at least one of a plasticizer(such, as for example, a citric acid ester or a phthalic acid ester), asurfactant (such as, for example, polysorbate 80 or sodium laurylsulfate), a glidant (such as, for example, talc or titanium dioxide), acoloring agent and a polishing agent.

The method for applying the enteric coating material to the substratecan vary. Substantially any coating method can be used, such as pancoating or fluidized bed coating, with the solution of the enteric coatchosen.

A preferred embodiment of the formulation of the present invention ispresented in Example 1 below. Residual alkalinizing agent in the coatingwas analyzed as described in Examples 2 and 3, respectively.

The following specific examples illustrate various aspects of thecompositions of the present invention, and are not intended to belimiting in any way. Specific reference is made to Omeprazole for thepurposes of description only and without intending to be limiting.

EXAMPLES Example 1: Delayed Release Tablets, 20 mg OTC Formulation

Pharmaceutical Amount Percent/ Ingredients function mg/tablet tabletActive constituent Omeprazole USP Active 20.00 6.51 Core Lactosemonohydrate NF Filler 203.00 66.12 Sodium starch disintegrant 10.00 3.25glycolate NF Sodium stearate NF alkalinizing agent 10.00 3.25 Sodiumstearyl lubricant 7.00 2.28 fumarate NF Coating Hypromellose acetateenteric coating polymer 32.00 10.42 succinate NF Triethyl citrate NFplasticizer 4.50 1.47 Sodium lauryl sulfate wetting agent 0.50 0.16 NFTalc USP Glidant 8.14 2.65 Strong ammonium alkalinizing agent NA* —solution NF Monoethanolamine NF alkalinizing agent 1.00 0.33 SepisperseAP 3527 coloring agent 10.80 3.52 Carnauba wax NF polishing agent 0.060.02 Purified water Solvent NA* — Total weight 307.00 Ca 100 *strongammonium solution is used as a volatile alkalizing agent which isevaporated during the coating process.

Preparation of the Substrate:

Omeprazole was thoroughly mixed with lactose, sodium starch glycolate,sodium stearate and sodium stearyl fumarate. The mixture was thencompressed into tablets weighing 250 mg each. The tablets were thentransferred into a conventional coating pan and coated with the entericcoating, prepared as described below.

Preparation of Enteric Coating

Coating A: triethyl citrate was dissolved in water, sodium laurylsulfate was then added to this solution, HPMCAS and talc were dispersedin this solution, such that the concentration of HPMCAS was about 7%weight per volume. Monoethanolamine was added to this dispersion Ammoniain a 25% solution was added to adjust the pH value in a range of fromabout 7 to about pH 9. The pigment was then added to the enteric coatingdispersion.Coating B: Triethyl citrate was dissolved in a mixture of isopropylalcohol and alcohol, sodium lauryl sulfate was then added to thissolution, HPMCAS and talc were dispersed in this solution, such that theconcentration of HPMCAS was about 6% weight per volume Ammonia in a 25%solution was added to adjust the pH value in a range of from about 7 toabout pH 9. The pigment was then added to the enteric coatingdispersion. The tablet cores were then transferred into a conventionalcoating pan and coated with the enteric coating layer.Coating C: Triethyl citrate was dissolved in water to form an aqueoussolution; sodium lauryl sulfate was then added to this aqueous solution.HPMCAS, colloidal silicon dioxide and talc were dispersed in thissolution, such that the concentration of HPMCAS was about 7% weight pervolume Ammonia in a 25% solution was added to adjust the pH value of thecoating dispersion in a range of from about 7 to about pH 9.Coating D: Triethyl citrate was dissolved in water to form an aqueoussolution; sodium lauryl sulfate was then added to this aqueous solution.HPMCAS, talc, and monoethanolamine were dispersed in this solution,Ammonia in a 25% solution was added to adjust the pH value of thecoating dispersion in a range of from about 7 to about pH 9.

Example 2: Omeprazole Delayed Release Tablets 20 mg—Determination ofAmmonia

Samples were stored at room temperature prior to analysis.

The samples were analyzed according to Standard Methods for Examinationof Water and Waste Water, Ed. 19, 1995, Method 4500-NH₃ F (phenatemethod). The samples were prepared in triplicate by adding 30 ml HPLCgrade water to one tablet, shaking overnight on an inverting shaker,followed by centrifugation at 4000 rpm for 15 minutes. This solution wasfiltered through 2 layers of glass fiber cartridge (GFC) filters andanalyzed according to the above mentioned method. Quantitation wasperformed using a calibration curve prepared from solutions of NH₄Cl inwater in the concentration range of 0.05 μg/mL to 1.0 μg/mL NH₃. Theuncoated tablets served as a control sample for the analysis of thecoated tablets.

Results are presented in Table 1.

TABLE 1 Batch No. (based on Lab no. Example 1) NH₃ mg/tablet 3789 BO415(coated) 0.011; 0.07; 0.011 Mean 0.010 3980 BO425 (coated) 0.09; 0.010;0.010 Mean 0.010 3981 BO515 (coated) 0.010; 0.012; 0.011 Mean 0.011

Example 3: Omeprazole Delayed Release Tablet 20 mg—Determination ofResidual Monoethanolamine

Samples were stored at room temperature prior to analysis.

Materials

Dansyl chloride Across 1158500 Sodium hydrogen carbonate Merck 106329Acetone J. T. Baker 9002 Acetonitrile J. T. Baker 9017 Sodium hydroxideJ. T. Baker 3722 Water HPLC grade Milli-Q in-house MonoethanolamineAnalyst sample 5015 Hydrochloric acid Riedel de Haen 30721

Equipment

Test tubes PP 50 ml Laboratory glassware Class A GFC filter paper 12.5cm Whatman 1822-125 Shaker Heidolf Centrifuge capable of maintaining4000 rpm

HPLC Instrument and Conditions

Apparatus: Agilent 1100 with variable wavelength detector andautosampler and Chemstation Rev A 10.01 software Column: Symmetry C 184.6 × 150 mm, 3.5 μ Injection volume: 10 μL Flow rate: 1.0 mL/minDetection: 254 nm Column temperature: ambient Run time: 10 minutesRetention time of −5.3 minutes MEA derivative:

Solutions

Hydrochloric acid 4 N was prepared by mixing 83.3 mL of concentratedhydrochloric acid (specific gravity 1.19, 37%) with 200 mL water in a250 mL volumetric flask. The volume was made up with water.

Dilute hydrochloric acid was prepared by adding 1.2 mL hydrochloric acid(specific gravity 1.19, 37%) to a 1 L volumetric flask containing about500 mL water, diluting to volume with water and mixing well.

Mobile phase was prepared by mixing 600 mL of water with 400 mLacetonitrile, mixing well and sonicating to degas.

0.2% dansyl chloride was prepared by weighing accurately about 100 mgdansyl chloride in a 50 mL volumetric flask and diluting with acetone.

0.1 M sodium hydrogen carbonate was prepared by weighing about 840 mg ofsodium hydrogen carbonate into a 100 mL volumetric flask, diluting withwater to give a pH of 9.0.

Monoethenolamine standard stock solution (1000 μg/mL) was prepared induplicate by weighing accurately about 100 mg of monoethanolamine into a100 ml volumetric flask, dissolving and diluting with water.

Monoethanolamine intermediate standard stock solution (100 μg/mL) wasprepared by adding 5.0 mL standard stock solution to a 50 mL volumetricflask with dilute hydrochloric acid.

Monoethanolamine working standard solution (10 μg/mL) was prepared fromintermediate standard stock solution by adding 5.0 mL to a 50 mLvolumetric flask with dilute hydrochloric acid.

Sample Preparation

Samples were prepared in duplicate. One tablet was placed per 50 mLconical test tube and 50 mL of water added. Test tubes were placed on aninverting shaker at speed 6 for 2-3 hours, until disintegration of thetablets, then acidified by adding 200 μL of 4 N HCl. Test tubes werecentrifuged for 15 minutes at 4000 rpm and filtered through Whatman GFC.

Derivatization Reaction

The procedure was performed on water as control and on all standards andsamples, directly in autosampler vials.

100 μL of water, standard or sample solution was mixed with 200 μL 0.2%dansyl chloride solution. 400 μL 0.1 M sodium hydrogen carbonate and 400μL acetone were added. The vials were closed, mixed and heated for 20minutes in a water bath at 60° C. The contents of the vials were cooledto room temperature and injected into the HPLC system.

Results are presented in Table 2.

TABLE 2 Lab no. Sample name Monoethanolamine mg/tablet 3789 BO415 0.77(% RSD = 6.0) 3980 BO425 0.730; 0.681 Mean 0.71 3981 BO515 0.822; 0.755Mean 0.79 5273 BO615 0.908; 0.780 Mean 0.84

Example 4: Suitability of Test Method for Determination of ResidualMonoethanolamine

In order to evaluate the suitability of the method as described above,the method was evaluated for specificity, linearity, precision (systemand method) and recovery.

In order to demonstrate the specificity, the following samples andsolutions were analyzed: a sample blank (water); a standard containing10 μg/mL monoethanolamine that had undergone the derivatizationprocedure; omeprazole tablets, prepared without the use ofmonoethanolamine, prepared according to the test method; and water.

Specificity

As shown in FIGS. 1 to 6, no interfering peaks at the retention time ofmonoethanolamine were recorded in the chromatograms of the blank sample,water, or the tablet without monoethanolamine.

Linearity

The linearity of the method was demonstrated in the range of from 1 to50 μg/mL monoethanolamine, corresponding to 0.05 to 2.5 mg/tablet.Results are presented in Table 3.

TABLE 3 Concentration (μg/mL) Peak area mAU*s % difference 0/967.4978E±00 43.7 1.92 1.5817E±01 10.9 4.81 4.4112E±01 −2.5 9.629.2365E±01 −6.0 19.24  2.0443 ± 02 −0.4 48.10  5.2640 ± 02 0.3correlation 0.99982 square correlation 0.99963 slope 1.1074E+01intercept −7.8104E+00   −7.6

Precision

The precision of the method was evaluated by replicate injections of astandard containing a nominal 10 μg/mL monoethanolamine derivatizedaccording to the test method (system precision) and by preparing asample of omeprazole tablets in 6 independent replicates according tothe test method (method precision).

The system precision results as presented in Table 4 show that goodprecision was obtained for the peak areas as well as for the retentiontimes.

TABLE 4 Replicate Retention time (min) Peak areas mAU*s 1 5.2919.0628E+01 2 5.286 8.9055E+01 3 5.283 9.1252E+01 4 5.283 8.8879E+01 55.262 8.9296E+01 6 5.225 9.0930E+01 Mean 5.272 9.0007E+01 % RSD 0.5 1.2

Method precision was performed using 6 preparations of omeprazoletablets (analyst sample 3789). Results were calculated against astandard containing 9.62 μg/mL monothenaolamine with an average peakarea of 9.5519E+01 mAU*s, using the following formula:

${{mg}\text{/}{tablet}} = \frac{{area}\mspace{14mu} {smp} \times {Cst} \times 50}{{area}\mspace{14mu} {st} \times 1000}$

area smp=monoethanolamine peak area in sample chromatogramarea st=average peak area of standard “10 μg/mL”cst=standard concentration in μg/mL50=sample extraction volume (mL)1000=conversion factor of μg to mg

A representative chromatogram is presented in FIG. 5.

Method precision data and results are presented in Table 5.

TABLE 5 Analyst Concentration of MEA in no. and Sample MEA peak MEA insample tablets replicate name area mAU*s solution (μg/mL) mg/tablet3789-1 coated 1.4518E+0.2 14.6 0.731 3789-2 BO4 15 1.6711E+0.2 16.80.842 3789-3 1.4151E+0.2 14.3 0.713 3789-4 1.5385E+0.2 15.5 0.775 3789-51.5710E+0.2 15.8 0.791 3789-6 1.5804E+0.2 15.9 0.796 MEAN 0.774 % RSD6.0

Recovery

The recovery of the method was demonstrated by spiking control (nomonoethanolamine) and monoethanolamine-containing omeprazole tabletswith three levels of monoethanolamine.

Omeprazole tablets containing monoethanolamine (sample 3789, batchBO415) were spiked at the 0.1% w/w level in triplicate. Omeprazolecontrol tablets (no MEA) were spiked at three levels with 0.15, 0.3 and0.9 mg/tablet, corresponding to 0.05, 0.1 and 0.3% w/w. The test wasperformed by transferring the tablets to 50 mL test tubes, addingsuitable volumes of a solution of 1000 μg/mL MEA, followed by 50 ml ofwater and preparation according to the method described above.

Results as presented in Tables 6 and 7 show good recovery results,within generally accepted limits for residue analysis. Recovery resultswere calculated against a standard containing 9.62 μg/mL MEA with anaverage peak area of 9.5519E+01 mAU*s. The recovery results in thetablets containing MEA were calculated as follows:

${\% \mspace{14mu} {recovery}} = \frac{{mg}\text{/}{tablet}\mspace{14mu} {found} \times 100}{{{average}\mspace{14mu} {mg}\text{/}{tablet}\mspace{14mu} ({unspiked})} + {{mg}\text{/}{tablet}\mspace{14mu} {added}}}$

A representative chromatogram of omeprazole tablets (analyst sample 3789Batch BO415) spiked with MEA is presented in FIG. 6.

TABLE 6 Concentration of MEA MEA peak Spiking in sample MEA Analyst No.Sample area level in solution in % and replicate name (mAu * s)mg/tablet (μg/mL) tablets recovery 5274-1 omeprazole 0.0000E+00 0.00.000 5274-2 20 mg 0.0000E+00 0.0 0.000 5274-3 uncoated 0.0000E+00 0.00.000 100605 Mean 0.000 5274-1 omeprazole 2.4417E+0.1 0.144 2.46 0.12385.5 5274-2 20 mg 2.4339E+01 2.45 0.123 85.2 5274-3 uncoated 2.4966E+012.51 0.126 87.4 100605 Mean 0.124 86.0 % RSD 1.4 1.4 5274-1 + 0.1%omeprazole 4.9693E+01 0.289 5.00 0.252 87.2 5274-2 + 0.1% 20 mg5.1115E+01 5.15 0.259 89.7 5274-3 + 0.1% uncoated 5.1356E+01 5.17 0.26090.1 100605 Mean 0.257 89.0 % RSD 1.8 1.8 5274-1 + 0.3% Omeprazole1.845E+02 0.962 18.59 0.948 98.5 5274-2 + 0.3% 20 mg 1.8919E+02 19.050.972 101.0 5274-3 + 0.3% uncoated 1.8982E+02 19.12 0.975 101.4 100605Mean 0.965 100.3 % RSD 1.5 1.5

TABLE 7 Concentration Analyst No. Spiking of MEA in MEA in and SampleMEA peak level sample solution tablet % replicate name area mAU * smg/tablet μg/mL mg/tablet recovery 3789-1 coated 1.4518E+02 14.6 0.7313789-2 BO415 1.6711E+02 16.8 0.842 3789-3 1.4151E+02 14.3 0.713 Mean0.762 % RSD 9.2 3789-1 + 0.1% coated 2.1507E+0.2 0.289 21.721.723.81.083 107.6 3789-2 + 0.1% B0415 2.1576E+0.2 1.086 107.9 3789-3 + 0.1%2.3641E+0.2 1.1190 118.2 Mean 1.120 111.2 % RSD 5.5 5.5

Standard and Sample Solution Stability

During the method development, stock solution stability was demonstratedfor 48 hours at room temperature. In addition, it was found that the MEAderivative is stable in autosampler vials at room temperature for atleast 48 hours, because the response of the MEA derivative did notchange upon reinjection.

Example 5: Omeprazole Delayed Release Tablets 20 mg—Determination ofFinal pH of Enteric Coating

Enteric coated omeprazole tablets were prepared according to thecomposition of Example 1 (Batch # BO425). The enteric coating wasprepared in aqueous dispersion, and the pH value of the coatingdispersion was adjusted to the range from about 7 to about pH 9 by acombination of monoethanolamine and concentrated ammonia solution. Theammonia solution evaporated during the coating process.

The pH of the coating layer following evaporation of the ammoniasolution was measured in the following test solutions:

-   -   1. Purified water (pH 5.9 at 22° C.), obtained from MILI Q        system; and    -   2. 1% buffer solution of Intestinal Fluid NF (pH 6.9 at 22° C.)        using potassium dihydrogenphosphate (lot # B36148 purchased from        Baker), and sodium hydroxide (lot # B452998549 from Merck), with        no pancreatin added.

For each test solution, three coated tablets were split and the core wasremoved by washing using purified water. The resulting film coats werethen transferred into a vial containing 30 ml test solution, and stirredfor 2 hours with a magnetic stirrer at 1000 rpm. The pH of the mediumwas determined.

It was found that in purified water, the coating films partiallydisintegrated and partially dissolved. The pH value of the medium wasfound to be 5.4.

In intestinal fluid, the coating films were fully disintegrated andfully dissolved (except for talc and the coloring powder of Sepisperse).The pH value of the medium was found to be 5.3. Hence, it is shown thatthe polymer retains its acidic properties and thus provides an acidicreaction.

Since the pH of the coating solution was initially basic, it can beconcluded that the change in pH occurs due to evaporation of ammoniasolution, causing the polymer, hydroxypropyl methylcellulose acetatesuccinate (HPMCAS) to revert to its acid form, having entericproperties. The acidic form of HPMCAS can be soluble in water onlythrough ionization of all free acidic groups in an aqueous medium withpH values above 5.5. This is in fact the reason that the polymer ischaracterized as an enteric polymer. While the native pH value of pureHPMCAS aqueous dispersion is about 4.5, the pH value of about 5.3 foundusing the composition of the present invention may be due to thepresence of residual monoethanolamine, which is used a second alkalizingagent for neutralization of HPMCAS.

The present study shows that when the entering coating polymer is placedin purified water as test medium, a partial dissolution of the polymerfirst takes place, which continues for as long as the pH of the mediumremains basic. Once the pH of the medium reaches an acidic value ofabout 5.4, dissolution of the polymer stops and the polymerdisintegrates. In diluted neutral buffer solution-1% simulatedintestinal fluid, on the other hand, an acidic pH was achieved onlyafter full polymer dissolution.

The temporarily neutralized HPMCAS coating prepared using a highconcentration of ammonia during the coating process provides an entericfilm coat surrounding the omeprazole-containing cores which canwithstand pH values of up to about 5. This can provide the activematerial with an appropriate protection while passing through thestomach even if the pH values of gastric fluid are elevated.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims. All publications, patents and patentapplications mentioned in this specification are herein incorporated intheir entirety by reference into the specification, to the same extentas if each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated herein byreference. In addition, citation or identification of any reference inthis application shall not be construed as an admission that suchreference is available as prior art to the present invention.

What is claimed is:
 1. A stable composition for a benzimidazolederivative, the composition comprising: a substrate, said substratecomprising the benzimidazole derivative, and a single coating layerconsisting essentially of one or more enteric polymers selected from thegroup consisting of cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate,cellulose acetate trimellitate, poly(methacrylic acid, methylmethacrylate (1:1)), poly(methacrylic acid, ethyl acrylate (1:1)),poly(methacrylic acid, methyl methacrylate (1:2)), hydroxypropylmethylcellulose acetate succinate (HPMCAS), sodium alginate, and alginicacid or mixtures thereof; the one or more enteric polymers beingneutralized by at least two alkalizing agents comprising at least onevolatile alkalizing agent prior to applying over the substrate to give apH of at least 6.5; wherein the alkalizing agents are selected from thegroup consisting of sodium hydroxide, potassium hydroxide, ammoniumhydroxide, methanolamine, monoethanol amine, propanolamine, arginine,lysine, methylene diamine, ethylene diamine, and propylene diamine;wherein said composition comprises less than 500 parts per million ofresidual volatile alkalizing agents relative to composition weight; andwherein the pH of said coating layer after being applied to saidsubstrate is in the range of from about 4.5 to about 6.5 as measured in30 ml of distilled water at 20-25° C.
 2. The composition of claim 1,wherein the pH of said coating layer after being applied to saidsubstrate is in the range of from about 5 to about
 6. 3. The compositionof claim 2, wherein the pH is about
 5. 4. The composition of claim 1,wherein said enteric polymer is dissolved in an organic solvent prior toapplication.
 5. The composition of claim 4, comprising less than about1000 parts per million of residual organic solvent.
 6. The compositionof claim 4, wherein said organic solvent is selected from the groupconsisting of acetone, ethanol, isopropanol and a mixture thereof. 7.The composition of claim 1, wherein said substrate is an active corecontaining the benzimidazole derivative.
 8. The composition of claim 7,wherein said active core is selected from the group consisting of apellet, a bead and a tablet.
 9. The composition of claim 8, wherein saidactive core is a tablet formed by compression.
 10. The composition ofclaim 1, wherein said substrate features: (i) a neutral core; and (ii)an active coating containing the benzimidazole derivative, said activecoating being layered over said neutral core; such that the compositionis in a form of a pellet.
 11. The composition of claim 1, wherein saidsubstrate features a core containing the benzimidazole derivative with asuitable binding agent, said core being prepared by spheronisation andpelletization; such that the composition is in a form of a pellet. 12.The composition of claim 1, wherein the benzimidazole derivative isselected from the group consisting of Omeprazole, Pantoprazole,Lansoprazole, Leminoprazole, Perprazole, Rabeprazole, andpharmaceutically acceptable salts thereof.
 13. The composition of claim1, wherein said substrate further comprises a filler.
 14. Thecomposition of claim 13, wherein said filler is selected from the groupconsisting of microcrystalline cellulose, sodium carboxymethylcellulose,ethylcellulose, cellulose acetate, starch, lactose, glucose, fructose,sucrose, dicalcium phosphate, sorbitol, mannitol, maltitol, lactitol,xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates, or amixture thereof.
 15. The composition of claim 1, wherein said substratefurther comprises a disintegrant.
 16. The composition of claim 15,wherein said disintegrant is selected from the group consisting oflow-substituted carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethylcellulose, pregelatinized starch, microcrystalline starch, waterinsoluble starch, calcium carboxymethyl cellulose, low substitutedhydroxypropyl cellulose, magnesium aluminum silicate, or a mixturethereof.
 17. The composition of claim 1, wherein said substrate furthercomprises a lubricant.
 18. The composition of claim 17, wherein saidlubricant is selected from the group consisting of sodium stearylfumarate, polyethylene glycol, silica colloidal anhydrous and magnesiumstearate, or a mixture thereof.
 19. The composition of claim 1, whereinsaid substrate further comprises an alkalizing agent.
 20. Thecomposition of claim 19, wherein said alkalizing agent is selected fromthe group consisting of sodium stearate, meglumine, disodium phosphate,and ammonia, or a mixture thereof.
 21. The composition of claim 1,wherein said coating layer further comprises a plasticizer.
 22. Thecomposition of claim 21, wherein said plasticizer is selected from thegroup consisting of a citric acid ester and a phthalic acid ester. 23.The composition of claim 1, wherein said coating layer further comprisesa surfactant.
 24. The composition of claim 23, wherein said surfactantis selected from the group consisting of polysorbate 80 and sodiumlauryl sulfate.
 25. The composition of claim 1, wherein said coatinglayer further comprises a glidant.
 26. The composition of claim 25,wherein said glidant is selected from the group consisting of talc andtitanium dioxide.
 27. The composition of claim 1, wherein said coatinglayer further comprises at least one of a coloring agent and a polishingagent.
 28. The composition of claim 1, wherein said single coating layerbeing neutralized by at least two alkalizing agents to give a pH in therange of from about 7 to about
 10. 29. The composition of claim 1,wherein said composition comprises between 6 to 500 parts per million ofresidual volatile alkalizing agents relative to composition weight. 30.The composition of claim 1, wherein said residual volatile alkalizingagent comprises an ammonia solution.
 31. A stable composition for abenzimidazole derivative, the composition comprising: a substrate, saidsubstrate comprising the benzimidazole derivative; and a single coatinglayer consisting essentially of at least one neutralized enteric polymercomprising hydroxypropyl methylcellulose acetate succinate (HPMCAS),wherein said enteric polymer is neutralized to a pH of at least 6.5 byat least two alkalizing agents prior to applying to said substrate,wherein the two alkalizing agents are selected from the group consistingof ammonium hydroxide, methanolamine, monoethanol amine, propanolamine,methylene diamine, ethylene diamine, propylene diamine, arginine andlysine, said single coating layer being layered directly over saidsubstrate, without an intermediate layer between said substrate and saidenteric coating, wherein said composition comprises less than about 500parts per million of residual volatile alkalizing agent relative to thetotal weight of the composition.
 32. The composition of claim 31,wherein said alkalizing agents are ammonium hydroxide and monoethanolamine.